This invention relates to a new one-step process for preparation of novel N-(acyloxyalkoxy)carbonyl derivatives useful as bioreversible prodrug moieties for primary and secondary amine functions in drugs.
For compounds which ionize, the rate of transport through biomembranes appear to be proportional to the concentration of undissociated molecules and the lipid solubility. It is often advantageous to perform derivatization of polar groups to aid absorption, since this would make the compounds more hydrophobic and hence more lipid soluble. Carbamylation confers such properties to amines since carbamates do not ionize. However, success with carbamate ester latentiation requires that it must be hydrolyzed to carbamic acid and an alcohol moiety after penetration through the biological barrier. This is especially true of carbamates of secondary amines, the rates of in vitro hydrolysis of which are 10.sup.5 -10.sup.9 times slower than that of the corresponding primary amines. In this regard, there does not appear to be a carbamate ester specific hydrolytic enzyme in mammals. Though cholinesterases hydrolyze carbamates and become reversibly inhibited in the process, the rates are too slow for practical use. Hence, modified carbamates with an enzymically hydrolyzable ester function were designed as prodrugs for amines. Esterase catalysed hydrolysis of the ester moiety triggers the regeneration of the parent amine from such derivates as depicted below. ##STR1## wherein RR'N, R.sub.1, R.sub.2 and R.sub.3 are as defined further along.
For the purposes of this specification, the term "prodrug" denotes a derivative of a known and proven primary or secondary amino functional drug (e.g. timolol, methyldopa, thiabendazole, etc.) which derivative, when administered to a warm-blooded animal, "cleaves" in such a manner as to release the proven drug form at its target site or sites of activity. The enzymatic and/or chemical hydrolytic "cleavage" of the compounds of the instant invention occurs in a manner such that the proven drug form is released while the remaining "cleaved" moiety remains nontoxic and is matabolized in such a manner that nontoxic, metabolic products are produced.